FGF acts as a co-transmitter through adenosine A(2A) receptor to regulate synaptic plasticity.
Abnormalities of striatal function have been implicated in several major neurological and psychiatric disorders, including Parkinson's disease, schizophrenia and depression. Adenosine, via activation of A(2A) receptors, antagonizes dopamine signaling at D2 receptors and A(2A) receptor antagonists have been tested as therapeutic agents for Parkinson's disease. We found a direct physical interaction between the G protein-coupled A(2A) receptor (A(2A)R) and the receptor tyrosine kinase fibroblast growth factor receptor (FGFR). Concomitant activation of these two classes of receptors, but not individual activation of either one alone, caused a robust activation of the MAPK/ERK pathway, differentiation and neurite extension of PC12 cells, spine morphogenesis in primary neuronal cultures, and cortico-striatal plasticity that was induced by a previously unknown A(2A)R/FGFR-dependent mechanism. The discovery of a direct physical interaction between the A(2A) and FGF receptors and the robust physiological consequences of this association shed light on the mechanism underlying FGF functions as a co-transmitter and open new avenues for therapeutic interventions.
Flajolet
Marc
M
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.
Wang
Zhongfeng
Z
Futter
Marie
M
Shen
Weixing
W
Nuangchamnong
Nina
N
Bendor
Jacob
J
Wallach
Iwona
I
Nairn
Angus C
AC
Surmeier
D James
DJ
Greengard
Paul
P
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D004622:Embryo, Mammalian; D005346:Fibroblast Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D047468:Immunoprecipitation / Q000379:methods; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D010627:Phenethylamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology; D013569:Synapses / Q000502:physiology*; D014162:Transfection / Q000379:methods; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D020798:Two-Hybrid System Techniques
D058908:Adenosine A2 Receptor Agonists; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; D017468:Receptors, Fibroblast Growth Factor; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D005346:Fibroblast Growth Factors; D000242:Cyclic AMP; D020794:Receptor Protein-Tyrosine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D000241:Adenosine